Protease-activated receptor 2 activation is sufficient to induce the transition to a chronic pain state

Pain
Dipti V TilluTheodore J Price

Abstract

Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is sufficient to induce a chronic pain state through extracellular signal-regulated kinase (ERK) signaling to protein synthesis machinery. We have further tested whether the maintenance of this chronic pain state involves a brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (trkB)/atypical protein kinase C (aPKC) signaling axis. We observed that intraplantar injection of the novel highly specific PAR2 agonist, 2-aminothiazol-4-yl-LIGRL-NH2 (2-at), evokes a long-lasting acute mechanical hypersensitivity (median effective dose ∼12 pmoles), facial grimacing, and causes robust hyperalgesic priming as revealed by a subsequent mechanical hypersensitivity and facial grimacing to prostaglandin E2 (PGE2) injection. The promechanical hypersensitivity effect of 2-at is completely absent in PAR2(-/-) mice as is hyperalgesic priming. Intraplantar injection of the upstream ERK inhibitor, U0126, and the eukaryotic initiation factor (eIF) 4F complex inhibitor, 4EGI-1, prevented the de...Continue Reading

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Citations

Jul 4, 2015·British Journal of Pharmacology·Scott BoitanoTheodore J Price
Feb 11, 2016·The Journal of Urology·Kenny RomanPraveen Thumbikat
Jul 20, 2016·Journal of Neurogastroenterology and Motility·Mohammad H FarzaeiRoja Rahimi
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Jan 12, 2021·The Journal of Pain : Official Journal of the American Pain Society·Juliet MwirigiTheodore J Price
Apr 4, 2021·Animals : an Open Access Journal From MDPI·Alexandra L WhittakerTimothy H Barker

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